Atherosclerosis

Trained immunity and atherosclerosis

Radboud university medical center, Nijmegen, the Netherlands

Research topic

Although the phenomenon of trained innate immunity (TRIM) is undoubtedly beneficial in the context of recurrent infections and vaccination, it might be detrimental in the context of chronic inflammatory disorders that are driven by chronic activation of the innate immune system.

Atherosclerosis is a chronic low-grade inflammatory disease of the arterial wall. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques, and orchestrate really the initiation, progression, and rupture of atherosclerotic plaques. We propose that the enhanced functional state of trained monocytes can accelerate the development of atherosclerosis. By this mechanism, stimuli that can induce TRIM (e.g. microbial products or endogenous pro-atherogenic compounds) can exert a long-term pro-atherogenic effect.

Our group aims at investigating the role of TRIM in atherogenesis from bench-to-bedside.

In isolated human monocytes, we brief stimulation with various microbial products (e.g. beta-glucan) induces a long-lasting pro-atherogenic phenotype that is characterized by increased production of pro-atherogenic cytokines and chemokines, increased foam cell formation, and increased production of proteases that can result in destabilization of atherosclerotic plaques. Interestingly, TRIM could also be induced by oxidized LDL particles and lipoprotein (a). Monocytes isolated from patients with elevated Lp(a) showed a trained immune phenotype, and this was associated with increased adherence to the vessel wall and increased arterial wall inflammation in vivo. In addition, monocytes isolated from patients with severe established atherosclerosis show a trained immune phenotype, both in terms of cytokine production, as well as in term of metabolic and epigenetic reprogramming.

In the next few years we aim to firmly establish the role of TRIM in the development of atherosclerosis in the context of various traditional and novel cardiovascular risk factors.